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TitleA point mutation in the nucleotide exchange factor eIF2B constitutively activates the integrated stress response by allosteric modulation.
Journal, issue, pagesElife, Vol. 11, Year 2022
Publish dateApr 13, 2022
AuthorsMorgane Boone / Lan Wang / Rosalie E Lawrence / Adam Frost / Peter Walter / Michael Schoof /
PubMed AbstractIn eukaryotic cells, stressors reprogram the cellular proteome by activating the integrated stress response (ISR). In its canonical form, stress-sensing kinases phosphorylate the eukaryotic ...In eukaryotic cells, stressors reprogram the cellular proteome by activating the integrated stress response (ISR). In its canonical form, stress-sensing kinases phosphorylate the eukaryotic translation initiation factor eIF2 (eIF2-P), which ultimately leads to reduced levels of ternary complex required for initiation of mRNA translation. Previously we showed that translational control is primarily exerted through a conformational switch in eIF2's nucleotide exchange factor, eIF2B, which shifts from its active A-State conformation to its inhibited I-State conformation upon eIF2-P binding, resulting in reduced nucleotide exchange on eIF2 (Schoof et al. 2021). Here, we show functionally and structurally how a single histidine to aspartate point mutation in eIF2B's β subunit (H160D) mimics the effects of eIF2-P binding by promoting an I-State like conformation, resulting in eIF2-P independent activation of the ISR. These findings corroborate our previously proposed A/I-State model of allosteric ISR regulation.
External linksElife / PubMed:35416150 / PubMed Central
MethodsEM (single particle)
Resolution2.8 Å
Structure data

EMDB-26098, PDB-7trj:
The eukaryotic translation initiation factor 2B from Homo sapiens with a H160D mutation in the beta subunit
Method: EM (single particle) / Resolution: 2.8 Å

Source
  • homo sapiens (human)
KeywordsTRANSLATION / integrated stress response

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